Field of the Invention
The present invention relates to inhibitors of the phosphodiesterase 4 (PDE4) enzyme. More particularly, the invention relates to compounds that are derivatives of 1-phenyl-2-pyridinyl alkyl alcohols, methods of preparing such a compound, compositions which contain such a compound, and therapeutic uses of such a compound.
Discussion of the Background
Airway obstruction characterizes a number of severe respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD). Events leading to airway obstruction include oedema of airway walls, increased mucous production and inflammation.
Drugs for treating respiratory diseases such as asthma and COPD are currently administered through inhalation. One of the advantages of the inhalatory route over the systemic one is the possibility of delivering the drug directly at site of action, reducing systemic side-effects, thus resulting in a more rapid clinical response and a higher therapeutic ratio.
Inhaled corticosteroids are the current maintenance therapy of choice for asthma and, together with bronchodilator beta2-agonists for acute symptom relief, they form the mainstay of current therapy for the disease. The current management of COPD is largely symptomatic by means of bronchodilating therapy with inhaled anticholinergics and inhaled beta2-adrenoceptor agonists. However, corticosteroids do not reduce the inflammatory response in COPD as they do in asthma.
Another class of therapeutic agents which has been widely investigated in view of its anti-inflammatory effects for the treatment of inflammatory respiratory diseases such as asthma and COPD is represented by the inhibitors of the enzymes phosphodiesterases (PDEs), in particular of the phosphodiesterase type 4 (hereinafter referred to as PDE4). Various compounds acting as PDE4 inhibitors have been disclosed in the prior art.
However, the usefulness of several PDE4 inhibitors of the first-generation such as rolipram and piclamilast has been limited due to their undesirable side effects. Said effects include nausea and emesis due to their action on PDE4 in the central nervous system and gastric acid secretion due to the action on PDE4 in parietal cells in the gut.
The cause of said side effects has been widely investigated.
It has been found that PDE4 exists in two distinct forms representing different conformations, that were designated as high affinity rolipram binding site or HPDE4, especially present in the central nervous system and in parietal cells, and low affinity rolipram binding site or LPDE4 (see Jacobitz, S et al Mol. Pharmacol, 1996, 50, 891-899, which is incorporated herein by reference in its entirety), which is found in the immune and inflammatory cells. While both forms appear to exhibit catalytic activity, they differ with respect to their sensitivity to inhibitors. In particular compounds with higher affinity for LPDE4 appear less prone to induce side-effects such as nausea, emesis and increased gastric secretion.
The effort of targeting LPDE4 has resulted in a slight improvement in the selectivity for the second-generation PDE4 inhibitors such as roflumilast. Nonetheless, roflumilast is under dosed in order to achieve an acceptable side effect profile.
Other classes of compounds acting as PDE4 inhibitors have been disclosed in the prior art.
For example, EP 1 634 606, which is incorporated herein by reference in its entirety, discloses, among others, ketone derivatives like benzofuran or 1,3-benzodioxole derivatives.
WO 94/02465, which is incorporated herein by reference in its entirety, discloses, among others, ketone derivatives of general formula
wherein R1 is lower alkyl and R2 may be alkyl, alkenyl, cycloalkyl, cycloalkyl, cycloalkenyl, cyclothioalkyl or cyclothioalkenyl.
WO 95/35281, which is incorporated herein by reference in its entirety, in the name of Celltech Therapeutics concerns tri-substituted phenyl derivatives.
WO2009/018909, which is incorporated herein by reference in its entirety, discloses derivatives of 1-phenyl-2-pyridinyl alkyl alcohols which have general formula below reported
as inhibitors of phosphodiesterase 4 (PDE4) enzyme.
WO2009/077068, which is incorporated herein by reference in its entirety, discloses further derivatives of 1-phenyl-2-pyridinyl alkyl alcohols which have general formula below reported
as inhibitors of phosphodiesterase 4 (PDE4) enzyme.
WO2010/089107, which is incorporated herein by reference in its entirety, discloses further derivatives of 1-phenyl-2-pyridinyl alkyl alcohols which have general formula below reported
as inhibitors of phosphodiesterase 4 (PDE4) enzyme.
Although several PDE4 inhibitors have been disclosed so far as above reported, there is still a need for further PDE4 inhibitors. Particularly, there is still a need for further PDE4 inhibitors endowed with a high affinity for PDE4 enzyme.
Particularly advantageous would also be the identification of further PDE4 inhibitors endowed both with a high affinity for PDE4 enzyme and good solubility in water and/or in aqueous system.
As such, besides of being used by inhalable preparations in form of dry powder inhaler, pressurized metered dosed inhaler, or propellant-free nebulized formulation, the said compounds, due to their absorbability and formulability, could also be administered by other routes such as oral or transdermal but also in any other pharmaceutical solutions such as, for instance, those for injectable, infusion or ocular administration.